RESUMEN
Mutations that perturb leptin-melanocortin signaling are known to cause hyperphagia and obesity, but energy expenditure has not been well studied outside rodents. We report on a common canine mutation in pro-opiomelanocortin (POMC), which prevents production of ß-melanocyte-stimulating hormone (ß-MSH) and ß-endorphin but not α-MSH; humans, similar to dogs, produce α-MSH and ß-MSH from the POMC propeptide, but rodents produce only α-MSH. We show that energy expenditure is markedly lower in affected dogs, which also have increased motivational salience in response to a food cue, indicating increased wanting or hunger. There was no difference in satiety at a modified ad libitum meal or in their hedonic response to food, nor disruption of adrenocorticotropic hormone (ACTH) or thyroid axes. In vitro, we show that ß-MSH signals comparably to α-MSH at melanocortin receptors. These data implicate ß-MSH and ß-endorphin as important in determining hunger and moderating energy expenditure and suggest that this role is independent of the presence of α-MSH.
Asunto(s)
betaendorfina , beta-MSH , Humanos , Perros , Animales , betaendorfina/genética , Metabolismo Basal , Proopiomelanocortina/genética , Hambre , alfa-MSH/genéticaRESUMEN
Although beta-endorphinergic neurons in the hypothalamic arcuate nucleus (ARC) synthesize beta-endorphin (ß-EP) to alleviate nociceptive behaviors, the underlying regulatory mechanisms remain unknown. Here, we elucidated an epigenetic pathway driven by microRNA regulation of ß-EP synthesis in ARC neurons to control neuropathic pain. In pain-injured rats miR-203a-3p was the most highly upregulated miRNA in the ARC. A similar increase was identified in the cerebrospinal fluid of trigeminal neuralgia patients. Mechanistically, we found histone deacetylase 9 was downregulated following nerve injury, which decreased deacetylation of histone H3 lysine-18, facilitating the binding of NR4A2 transcription factor to the miR-203a-3p gene promoter, thereby upregulating miR-203a-3p expression. Further, increased miR-203a-3p was found to maintain neuropathic pain by targeting proprotein convertase 1, an endopeptidase necessary for the cleavage of proopiomelanocortin, the precursor of ß-EP. The identified mechanism may provide an avenue for the development of new therapeutic targets for neuropathic pain treatment.
Asunto(s)
MicroARNs , Neuralgia , Animales , Humanos , Ratas , Núcleo Arqueado del Hipotálamo/metabolismo , betaendorfina/genética , betaendorfina/metabolismo , Epigénesis Genética , MicroARNs/genética , MicroARNs/metabolismo , Neuralgia/genética , Neuralgia/metabolismo , Neuronas/metabolismo , Roedores/genéticaRESUMEN
ß-endorphin (ß-EP) is involved in the regulation of male germ cells; however, little is known about the effect of ß-EP on primary germ cells via opioid receptors. In this study, we first revealed significant cell apoptosis in the testis of male rats after ß-EP intervention. Subsequently, the expression of the mu opioid receptor (MOR) was detected in both Leydig cells (LCs) and spermatogonia (SGs) by fluorescence colocalization; overlapping signals were also detected in apoptotic cells. In addition, LCs and SGs were separated from the testis of male rats and primary cells were treated with ß-EP; this increased the mRNA levels of MOR and was accompanied by acute cell apoptosis. Our findings provide a foundation for the further study of apoptosis in reproductive cells regulated by ß-EP and the MOR receptor.
Asunto(s)
Testículo , betaendorfina , Ratas , Animales , Masculino , Testículo/metabolismo , betaendorfina/genética , betaendorfina/metabolismo , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Células Intersticiales del Testículo/metabolismo , ApoptosisRESUMEN
The study aimed to examine the genetic contribution to buprenorphine (BUP) treatment in individuals with opioid use disorder (OUD), with a specific focus on BDNF and OPRM1 genes. A total of 113 controls and 111 OUD patients receiving sublingual BUP/naloxone were enrolled. OPRM1 A118G and BDNF Val66Met polymorphisms were investigated by PCR-FRLP. Plasma BDNF and beta-endorphin levels were assessed by ELISA kits in both groups. Blood BUP levels were measured by LC-MS/MS and normalized with daily BUP dose (BUP/D). OPRM1 A118G and BDNF Val66Met polymorphisms didn't have an effect on plasma beta-endorphin and BDNF levels in OUD patients, respectively. Interestingly, OUD patients had significantly higher plasma BDNF and lower beta-endorphin levels compared to the controls (p < 0.001). A negative and significant correlation between plasma BUP/D and BDNF levels was found. Age onset of first use was associated with OPRM1 A118G polymorphism. The findings indicated that sublingual BUP/naloxone may increase plasma BDNF levels, but may decrease beta-endorphin levels in individuals with OUD. Plasma BDNF level seemed to be decreased in a BUP/D concentration-dependent manner.
Asunto(s)
Buprenorfina , Trastornos Relacionados con Opioides , Factor Neurotrófico Derivado del Encéfalo/genética , Buprenorfina/uso terapéutico , Combinación Buprenorfina y Naloxona/uso terapéutico , Cromatografía Liquida , Humanos , Trastornos Relacionados con Opioides/complicaciones , Trastornos Relacionados con Opioides/tratamiento farmacológico , Trastornos Relacionados con Opioides/genética , Receptores Opioides mu/genética , Receptores Opioides mu/uso terapéutico , Espectrometría de Masas en Tándem , betaendorfina/genética , betaendorfina/uso terapéuticoRESUMEN
Despite the well-recognized effects of endogenous opioids on mood and behavior, research on its role in bipolar disorder (BD) is still limited to small or anecdotal reports. Considering that Beta-endorphins (ß-END) and Mu-opioid receptors (MOR), in particular, have a crucial activity in affective modulation, we hypothesized their alteration in BD. A cross-sectional study was conducted. We compared: (1) BD type I (BD-I) patients (n = 50) vs healthy controls (n = 27), (2) two BD-I subject subgroups: manic (MAN; n = 25) vs depressed (DEP; n = 25) subjects. Plasma levels of ß-END and MOR gene expression in peripheral blood mononuclear cells were analyzed using ELISA Immunoassay qRT-PCR. We found that subjects with BD exhibited a significant upregulation of MOR gene expression and a decrease of ß-END (p<0.0001 for both). MAN display higher MOR levels than DEP (p<0.001) and HC (p<0.0001). Plasma levels of ß-END were lower in DEP compared to MAN (p<0.05) and HC (p<0.0001). The main limitations are the cross-sectional design and the lack of a group of euthymic subjects. Although preliminary, our results suggest a dysregulation of the endogenous opioid systems in BD. In particular, both MAN and DEP showed a reduction of ß-END levels, whereas MAN was associated with MOR gene overexpression.
Asunto(s)
Trastorno Bipolar , betaendorfina , Trastorno Bipolar/genética , Estudios Transversales , Expresión Génica , Humanos , Leucocitos Mononucleares/metabolismo , Receptores Opioides mu/genética , betaendorfina/genética , betaendorfina/metabolismoRESUMEN
Opioid peptides and their receptors are expressed in the mammalian retina; however, little is known about how they might affect visual processing. The melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs), which mediate important non-image-forming visual processes such as the pupillary light reflex (PLR), express ß-endorphin-preferring, µ-opioid receptors (MORs). The objective of the present study was to elucidate if opioids, endogenous or exogenous, modulate pupillary light reflex (PLR) via MORs expressed by ipRGCs. MOR-selective agonist [D-Ala2, MePhe4, Gly-ol5]-enkephalin (DAMGO) or antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) was administered via intravitreal injection. PLR was recorded in response to light stimuli of various intensities. DAMGO eliminated PLR evoked by light with intensities below melanopsin activation threshold but not that evoked by bright blue irradiance that activated melanopsin signaling, although in the latter case, DAMGO markedly slowed pupil constriction. CTAP or genetic ablation of MORs in ipRGCs slightly enhanced dim-light-evoked PLR but not that evoked by a bright blue stimulus. Our results suggest that endogenous opioid signaling in the retina contributes to the regulation of PLR. The slowing of bright light-evoked PLR by DAMGO is consistent with the observation that systemically applied opioids accumulate in the vitreous and that patients receiving chronic opioid treatment have slow PLR.
Asunto(s)
Péptidos Opioides/genética , Receptores Opioides mu/genética , Retina/metabolismo , Percepción Visual/genética , Animales , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Encefalinas/antagonistas & inhibidores , Encefalinas/genética , Humanos , Luz , Ratones , Péptidos/farmacología , Receptores Opioides/genética , Receptores Opioides mu/antagonistas & inhibidores , Reflejo/genética , Retina/patología , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/fisiología , Transducción de Señal/efectos de los fármacos , Percepción Visual/efectos de los fármacos , betaendorfina/genéticaRESUMEN
In the pituitary gland, hormones are stored in a functional amyloid state within acidic secretory granules before they are released into the blood. To gain a detailed understanding of the structure-function relationship of amyloids in hormone secretion, the three-dimensional (3D) structure of the amyloid fibril of the human hormone ß-endorphin was determined by solid-state NMR. We find that ß-endorphin fibrils are in a ß-solenoid conformation with a protonated glutamate residue in their fibrillar core. During exocytosis of the hormone amyloid the pH increases from acidic in the secretory granule to neutral level in the blood, thus it is suggested-and supported with mutagenesis data-that the pH change in the cellular milieu acts through the deprotonation of glutamate 8 to release the hormone from the amyloid. For amyloid disassembly in the blood, it is proposed that the pH change acts together with a buffer composition change and hormone dilution. In the pituitary gland, peptide hormones can be stored as amyloid fibrils within acidic secretory granules before release into the blood stream. Here, we use solid-state NMR to determine the 3D structure of the amyloid fiber formed by the human hormone ß-endorphin. We find that ß-endorphin fibrils are in a ß-solenoid conformation that is generally reminiscent of other functional amyloids. In the ß-endorphin amyloid, every layer of the ß-solenoid is composed of a single peptide and protonated Glu8 is located in the fibrillar core. The secretory granule has an acidic pH but, on exocytosis, the ß-endorphin fibril would encounter neutral pH conditions (pH 7.4) in the blood; this pH change would result in deprotonation of Glu8 to release the hormone peptide from the amyloid. Analyses of ß-endorphin variants carrying mutations in Glu8 support the role of the protonation state of this residue in fibril disassembly, among other environmental changes.
Asunto(s)
Amiloide/química , Ácido Glutámico/química , Neurotransmisores/química , Protones , betaendorfina/química , Secuencia de Aminoácidos , Amiloide/genética , Amiloide/metabolismo , Clonación Molecular , Escherichia coli/genética , Escherichia coli/metabolismo , Expresión Génica , Vectores Genéticos/química , Vectores Genéticos/metabolismo , Ácido Glutámico/metabolismo , Humanos , Enlace de Hidrógeno , Concentración de Iones de Hidrógeno , Modelos Moleculares , Mutación , Neurotransmisores/genética , Neurotransmisores/metabolismo , Resonancia Magnética Nuclear Biomolecular , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alineación de Secuencia , Homología de Secuencia de Aminoácido , betaendorfina/genética , betaendorfina/metabolismoRESUMEN
OBJECTIVES: To assess the protective effect of the glucagon-like peptide-1 receptor (GLP-1R) agonist morroniside against neuropathic pain and its downstream mechanisms of activating microglial GLP-1R/interleukin-10 (IL-10)/ß-endorphin antinociceptive pathway. METHODS: Spinal nerve ligation-induced neuropathic pain rats were intrathecally injected with morroniside, with mechanical paw withdrawal threshold being assessed. The expression of spinal and cultured microglia IL-10 and ß-endorphin were detected with qRT-PCR. KEY FINDINGS: Morroniside alleviated mechanical allodynia in neuropathic rats, which was blocked by inhibiting or depleting microglia. In addition, neutralizing spinal IL-10 or ß-endorphin with specialized antibodies or blocking the µ-opioid receptor was able to fully reverse the morroniside-induced mechanical antiallodynia. Morroniside treatment stimulated the gene expression of IL-10 and ß-endorphin in the spinal lumbar enlargements of neuropathic rats as well as in primary cultured microglia. Furthermore, pretreatment with the IL-10 antibody blocked morroniside-stimulated ß-endorphin expression in the spinal cords of neuropathic rats and cultured primary microglia, whereas the ß-endorphin antibody failed to affect morroniside-stimulated gene expression of IL-10. CONCLUSIONS: These results reveal that morroniside produces therapeutic effects in neuropathy through spinal microglial expression of IL-10 and subsequent ß-endorphin after activation of GLP-1R.
Asunto(s)
Analgésicos/farmacología , Péptido 1 Similar al Glucagón/agonistas , Glicósidos/farmacología , Interleucina-10/genética , Neuralgia/tratamiento farmacológico , betaendorfina/genética , Analgésicos/uso terapéutico , Animales , Células Cultivadas , Glicósidos/uso terapéutico , Masculino , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Neuralgia/genética , Neuralgia/patología , Ratas , Ratas Wistar , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Médula Espinal/patología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Lemairamin (also known as wgx-50), is isolated from the pericarps of the Zanthoxylum plants. As an agonist of α7 nicotinic acetylcholine receptors (α7nAChRs), it can reduce neuroinflammation in Alzheimer's disease. This study evaluated its antinociceptive effects in pain hypersensitivity and explored the underlying mechanisms. The data showed that subcutaneous lemairamin injection dose-dependently inhibited formalin-induced tonic pain but not acute nociception in mice and rats, while intrathecal lemairamin injection also dose-dependently produced mechanical antiallodynia in the ipsilateral hindpaws of neuropathic and bone cancer pain rats without affecting mechanical thresholds in the contralateral hindpaws. Multiple bi-daily lemairamin injections for 7 days did not induce mechanical antiallodynic tolerance in neuropathic rats. Moreover, the antinociceptive effects of lemairamin in formalin-induced tonic pain and mechanical antiallodynia in neuropathic pain were suppressed by the α7nAChR antagonist methyllycaconitine. In an α7nAChR antagonist-reversible manner, intrathecal lemairamin also stimulated spinal expression of IL-10 and ß-endorphin, while lemairamin treatment induced IL-10 and ß-endorphin expression in primary spinal microglial cells. In addition, intrathecal injection of a microglial activation inhibitor minocycline, anti-IL-10 antibody, anti-ß-endorphin antiserum or µ-opioid receptor-preferred antagonist naloxone was all able to block lemairamin-induced mechanical antiallodynia in neuropathic pain. These data demonstrated that lemairamin could produce antinociception in pain hypersensitivity through the spinal IL-10/ß-endorphin pathway following α7nAChR activation.
Asunto(s)
Acrilamidas/farmacología , Analgésicos/farmacología , Dolor en Cáncer/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Microglía/efectos de los fármacos , Neuralgia/tratamiento farmacológico , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Aconitina/análogos & derivados , Aconitina/farmacología , Acrilamidas/administración & dosificación , Acrilamidas/uso terapéutico , Analgésicos/administración & dosificación , Analgésicos/uso terapéutico , Animales , Femenino , Formaldehído , Hiperalgesia/genética , Hiperalgesia/metabolismo , Inyecciones Espinales , Interleucina-10/genética , Interleucina-10/metabolismo , Masculino , Ratones , Microglía/metabolismo , Minociclina/administración & dosificación , Naloxona/administración & dosificación , Ratas , Ratas Wistar , Médula Espinal/metabolismo , Zanthoxylum/química , Zanthoxylum/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7/genética , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , betaendorfina/genética , betaendorfina/metabolismoRESUMEN
ß-Endorphin exerts a broad spectrum of physiological activity on mood, immune functions, pain management, reward effects, and behavioral stability. ß-Endorphin is produced in certain neurons within the central and peripheral nervous system but also in the skin, especially in response to ultraviolet radiation. In the present study we have investigated the impact of visible blue light at λâ¯=â¯453â¯nm (BL) on ß-endorphin production of primary human skin keratinocytes (hKC) in-vitro as well as on systemic ß-endorphin formation of whole-body exposed subjects in-vivo. We found that BL irradiation significantly enhanced both keratinocytic ß-endorphin production of hKC cultures as well as systemic ß-endorphin concentrations in light exposed healthy subjects. Interestingly, in hKC cultures elevated ß-endorphin formation was paralleled by significantly increased levels of non-enzymatically generated nitric oxide (NO), whereas elevated systemic ß-endorphin values of BL-exposed subjects were accompanied by enhanced systemic concentration of bioactive NO-derivates. These findings point to a pivotal role of NO in the molecular mechanism of the observed BL-induced effects, and indeed, exogenously applied NO was able to significantly enhance ß-endorphin production in hKC cultures. Thus, our finding of BL-induced increases in systemic ß-endorphin concentration in-vivo can be plausibly explained by an event sequence comprising 1.) BL-driven non-enzymatic formation of NO in the exposed skin tissue, 2.) systemic distribution of cutaneously produced NO in the form of bioactive nitroso compounds, 3.) a subsequent NO-dependent induction of ß-endorphin synthesis in epidermal keratinocytes, and 4.) probably also a NO-dependent modulation of ß-endorphin synthesis in specialized neurons within the central and peripheral nervous system.
Asunto(s)
Queratinocitos/metabolismo , Óxido Nítrico/química , Piel/metabolismo , betaendorfina/genética , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/efectos de la radiación , Humanos , Queratinocitos/efectos de la radiación , Luz , Óxido Nítrico/genética , Óxido Nítrico/efectos de la radiación , Piel/crecimiento & desarrollo , Piel/efectos de la radiación , Rayos Ultravioleta/efectos adversos , betaendorfina/biosíntesisRESUMEN
BACKGROUND: Opioid-primed relapse is a global burden. Although current strategies have improved, optimal therapy is urgently needed. METHODS: A recombinant adenovirus (Ad-NEP) expressing ß-endorphin (ß-EP) was designed and injected intracerebroventricularly (icv) into the right lateral ventricle in rats. Spatial and temporal ß-EP expression in the lateral ventricle wall, subventricular zone and adjacent choroid plexus and the ß-EP concentration in the cerebrospinal fluid (CSF) were observed during a 21-day period. A morphine priming-induced conditioned place preference (CPP) rat model was established. The ß-EP-ir neuron counts, CSF ß-EP concentration, and CPP score, which were used to evaluate morphine-primed reinstatement following extinction, were recorded 7 days after the icv injection. Additionally, the rats were pretreated with the irreversible µ opioid receptor antagonist ß-funaltrexamine (ß-FNA) and the selective κ opioid receptor antagonist nor-binaltorphimine (nor-BNI) to identify the receptor-dependent mechanism. RESULTS: Both peak ß-EP expression in target neurons and the peak CSF ß-EP concentration occurred 7 to 8 days after Ad-NEP icv injection. The sustainable increase in the CSF ß-EP concentration was correlated with a decrease in the CPP score 7 days after the Ad-NEP icv injection. Furthermore, reinstatement was almost reversed by ß-FNA pretreatment 24 hours before the behavioral test, but nor-BNI had little effect. CONCLUSION: The increasing cerebrospinal fluid ß-endorphin concentrations showed that the therapeutic effect on opioid relapse occurred predominantly through a µ opioid receptor-dependent mechanism. The Ad-NEP adenovirus can be considered an alternative therapy for opioid relapse.
Asunto(s)
Conducta Animal/efectos de los fármacos , Morfina/administración & dosificación , Narcóticos/farmacología , Receptores Opioides mu/efectos de los fármacos , betaendorfina/líquido cefalorraquídeo , betaendorfina/genética , Adenoviridae/genética , Animales , Animales Modificados Genéticamente , Ventrículos Laterales/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-Dawley , Recurrencia , Prevención SecundariaRESUMEN
BACKGROUND: Endogenous ß-endorphin is delivered exclusively from the pituitary gland in various stressful conditions and plays an essential role in the nervous system. Recently, a few studies demonstrated peripheral endogenous opioid secretion from immune cells at inflammatory sites. Here, we investigated the expression of ß-endorphin, the most powerful endogenous opioid peptide, in peripheral tissues in response to systemic administration of lipopolysaccharide in mice. METHODS: Male C57BL/6N mice received intravenously administered lipopolysaccharide to induce an endotoxic shock-like condition. mRNA for proopiomelanocortin, a precursor of ß-endorphin, was quantified in peripheral blood cells, liver and spleen. ß-endorphin peptide was measured in the liver and spleen. RESULTS: Expression of proopiomelanocortin mRNA was detected in peripheral tissues after systemic administration of lipopolysaccharide. Lipopolysaccharide also induced ß-endorphin expression in the liver and spleen. CONCLUSION: Expression of proopiomelanocortin mRNA and ß-endorphin was detected in peripheral tissues after systemic administration of lipopolysaccharide. These results provide new evidence that peripheral endogenous opioids can be produced not only as a result of local inflammation but also by severe systemic stress such as endotoxic shock. Further study is required to clarify the role of peripheral ß-endorphin during endotoxic shock.
Asunto(s)
Lipopolisacáridos/administración & dosificación , Choque Séptico/inducido químicamente , Choque Séptico/genética , betaendorfina/genética , Animales , Células Sanguíneas/efectos de los fármacos , Células Sanguíneas/metabolismo , Modelos Animales de Enfermedad , Expresión Génica/efectos de los fármacos , Inflamación/inducido químicamente , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , Choque Séptico/metabolismo , Choque Séptico/patología , Bazo/efectos de los fármacos , Bazo/metabolismo , Bazo/patología , Distribución Tisular/efectos de los fármacos , betaendorfina/metabolismoRESUMEN
The review provides information about the features of the sensitivity of thymocytes, lymphoid organs' cells and T-lymphocytes of peripheral blood to the hormones secreted by anterior pituitary gland's cells: growth hormone, thyrotropin, adrenocorticotropic hormone, prolactin and ß-endorphin. Some aspects of the T-lymphocytes's response to humoral signals from the hypophysis are shown in the article. Also the pituitary hormones' role in the regulation of proliferation, differentiation, and cytokine production of T-lymphocytes in normal and pathological conditions of the organism being discussed.
Asunto(s)
Hormona Adrenocorticotrópica/farmacología , Hormona del Crecimiento/farmacología , Adenohipófisis/metabolismo , Prolactina/farmacología , Timocitos/efectos de los fármacos , Tirotropina/farmacología , betaendorfina/farmacología , Hormona Adrenocorticotrópica/genética , Hormona Adrenocorticotrópica/inmunología , Animales , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación de la Expresión Génica , Hormona del Crecimiento/genética , Hormona del Crecimiento/inmunología , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Cultivo Primario de Células , Prolactina/genética , Prolactina/inmunología , Transducción de Señal , Timocitos/citología , Timocitos/inmunología , Tirotropina/genética , Tirotropina/inmunología , betaendorfina/genética , betaendorfina/inmunologíaRESUMEN
The glucagon-like peptide-1 (GLP-1) receptor agonist exenatide stimulates microglial ß-endorphin expression and subsequently produces neuroprotection and antinociception. This study illustrated an unrecognized autocrine role of IL-10 in mediation of exenatide-induced ß-endorphin expression. Treatment with exenatide in cultured primary spinal microglia concentration dependently stimulated the expression of the M2 microglial markers IL-10, IL-4, Arg 1, and CD206, but not the M1 microglial markers TNF-α, IL-1ß, IL-6, or CD68. Intrathecal exenatide injection also significantly upregulated spinal microglial expression of IL-10, IL-4, Arg 1, and CD206, but not TNF-α, IL-1ß, IL-6, or CD68. Intrathecal injection of exenatide stimulated spinal microglial expression of IL-10 and ß-endorphin in neuropathic rats. Furthermore, treatment with IL-10 (but not IL-4) stimulated ß-endorphin expression in cultured primary microglia, whereas treatment with ß-endorphin failed to increase IL-10 expression. The IL-10-neutralizing antibody entirely blocked exenatide-induced spinal microglial expression of ß-endorphin in vitro and in vivo and fully blocked exenatide mechanical antiallodynia in neuropathic rats. Moreover, specific cAMP/PKA/p38 signal inhibitors and siRNA/p38ß, but not siRNA/p38α, completely blocked exenatide-induced IL-10 expression in cultured primary microglia. Knock-down of IL-10 receptor-α mRNA using siRNA fully inhibited exenatide-induced spinal microglial ß-endorphin expression and mechanical antiallodynia in neuropathy. Exenatide also markedly stimulated phosphorylation of the transcription factor STAT3 in cultured primary microglia and ß-endorphin stimulation was completely inhibited by the specific STAT3 activation inhibitor. These results revealed that IL-10 in microglia mediated ß-endorphin expression after GLP-1 receptor activation through the autocrine cAMP/PKA/p38ß/CREB and subsequent IL-10 receptor/STAT3 signal pathways.SIGNIFICANCE STATEMENT Activation of GLP-1 receptors specifically and simultaneously stimulates the expression of anti-inflammatory cytokines IL-10 and IL-4, as well as the neuroprotective factor ß-endorphin from microglia. GLP-1 receptor agonism induces ß-endorphin expression and antinociception through autocrine release of IL-10. Activation of GLP-1 receptors stimulates IL-10 and ß-endorphin expression subsequently through the Gs-cAMP/PKA/p38ß/CREB and IL-10/IL-10 receptor-α/STAT3 signal transduction pathways.
Asunto(s)
Comunicación Autocrina/fisiología , Receptor del Péptido 1 Similar al Glucagón/biosíntesis , Interleucina-10/biosíntesis , Microglía/metabolismo , Médula Espinal/metabolismo , betaendorfina/biosíntesis , Animales , Animales Recién Nacidos , Comunicación Autocrina/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Exenatida , Expresión Génica , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/genética , Interleucina-10/genética , Interleucina-10/farmacología , Masculino , Microglía/efectos de los fármacos , Péptidos/farmacología , Ratas , Ratas Wistar , Médula Espinal/citología , Médula Espinal/efectos de los fármacos , Ponzoñas/farmacología , betaendorfina/genéticaRESUMEN
There is growing evidence that the number and quality of social relationships have substantial impacts on health, well-being, and longevity, and, at least in animals, on reproductive fitness. Although it is widely recognized that these outcomes are mediated by a number of neuropeptides, the roles these play remain debated. We suggest that an overemphasis on one neuropeptide (oxytocin), combined with a failure to distinguish between different social domains, has obscured the complexity involved. We use variation in 33 SNPs for the receptor genes for six well-known social neuropeptides in relation to three separate domains of sociality (social disposition, dyadic relationships, and social networks) to show that three neuropeptides (ß-endorphin, oxytocin, and dopamine) play particularly important roles, with each being associated predominantly with a different social domain. However, endorphins and dopamine have a much wider compass than oxytocin (whose effects are confined to romantic/reproductive relationships and often do not survive control for other neuropeptides). In contrast, vasopressin, serotonin, and testosterone play only limited roles.
Asunto(s)
Receptores Dopaminérgicos/genética , Receptores Opioides/genética , Receptores de Oxitocina/genética , Adolescente , Adulto , Anciano , Encéfalo/metabolismo , Dopamina/genética , Dopamina/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuropéptidos/genética , Neuropéptidos/metabolismo , Oxitocina/genética , Oxitocina/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores Opioides/metabolismo , Saliva , Conducta Social , Red Social , Apoyo Social , betaendorfina/genética , betaendorfina/metabolismoRESUMEN
Immune cell-derived beta-endorphin (END) and other opioid peptides elicit potent and clinically relevant inhibition of pain (analgesia) in inflamed tissue by activation of peripheral opioid receptors. Pro-opiomelanocortin (POMC) is the polypeptide precursor of END and is processed by prohormone convertases (PCs). This study aims to decipher the processing of POMC in lymphocyte subsets in a rat model of unilateral painful hindpaw inflammation. Lymphocytes, isolated from popliteal lymph nodes, were separated into B-cells, T-cells, T-helper cells and cytotoxic T-cells using magnetic cell sorting, and were examined by polymerase chain reaction, immunofluorescence and radioimmunoassay. At 2 h of inflammation, POMC exon 2-3 mRNA was mostly expressed in B- but not in T-cells. Prohormone convertase 1 (PC1) mRNA and protein were upregulated in B-cells and T-helper cells. Prohormone convertase 2 (PC2) was expressed in T- and B-cells, both in inflamed and non-inflamed lymph nodes. END was expressed in B- but not in T-cells. We conclude that POMC, its processing enzymes and END are predominantly expressed in B-lymphocytes at 2 h of paw inflammation.
Asunto(s)
Linfocitos B/metabolismo , Dolor/metabolismo , Proopiomelanocortina/biosíntesis , ARN Mensajero/biosíntesis , Serina Endopeptidasas/biosíntesis , betaendorfina/biosíntesis , Animales , Linfocitos B/enzimología , Expresión Génica , Inflamación/genética , Inflamación/metabolismo , Masculino , Dolor/genética , Proopiomelanocortina/genética , Proproteína Convertasa 1/biosíntesis , Proproteína Convertasa 1/genética , Proproteína Convertasa 2/biosíntesis , Proproteína Convertasa 2/genética , ARN Mensajero/genética , Ratas , Ratas Wistar , Serina Endopeptidasas/genética , betaendorfina/genéticaRESUMEN
Neuropathic pain often results from peripheral nerve damage, which can involve immune response. Local leukocyte-derived opioid peptides or exogenous opioid agonists inhibit neuropathy-induced mechanical hypersensitivity in animal models. Since neuropathic pain can also be augmented by heat, in this study we investigated the role of opioids in the modulation of neuropathy-evoked heat hypersensitivity. We used a chronic constriction injury of the sciatic nerve in wild-type and opioid peptide-knockout mice, and tested opioid effects in heat and mechanical hypersensitivity using Hargreaves and von Frey tests, respectively. We found that although perineural exogenous opioid agonists, including peptidergic ligands, were effective, the endogenous opioid peptides ß-endorphin, Met-enkephalin and dynorphin A did not alleviate heat hypersensitivity. Specifically, corticotropin-releasing factor, an agent triggering opioid peptide secretion from leukocytes, applied perineurally did not attenuate heat hypersensitivity in wild-type mice. Exogenous opioids, also shown to release opioid peptides via activation of leukocyte opioid receptors, were equally analgesic in wild-type and opioid peptide-knockout mice, indicating that endogenous opioids do not contribute to exogenous opioid analgesia in heat hypersensitivity. Furthermore, exogenously applied opioid peptides were ineffective as well. Conversely, opioid peptides relieved mechanical hypersensitivity. Thus, both opioid type and sensory modality may determine the outcome of neuropathic pain treatment.
Asunto(s)
Analgésicos Opioides/farmacología , Neuralgia/tratamiento farmacológico , Neuralgia/etiología , Péptidos Opioides/metabolismo , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Animales , Hormona Liberadora de Corticotropina/farmacología , Dinorfinas/genética , Dinorfinas/metabolismo , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Encefalina D-Penicilamina (2,5)/farmacología , Encefalina Metionina/genética , Encefalina Metionina/metabolismo , Encefalina Metionina/farmacología , Calor/efectos adversos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Neuralgia/genética , Péptidos Opioides/genética , Sistema Nervioso Periférico/metabolismo , Receptores Opioides/agonistas , betaendorfina/genética , betaendorfina/metabolismo , betaendorfina/farmacologíaRESUMEN
Lamiophlomis rotata (L. rotata, Duyiwei) is an orally available Tibetan analgesic herb widely prescribed in China. Shanzhiside methylester (SM) is a principle effective iridoid glycoside of L. rotata and serves as a small molecule glucagon-like peptide-1 (GLP-1) receptor agonist. This study aims to evaluate the signal mechanisms underlying SM anti-allodynia, determine the ability of SM to induce anti-allodynic tolerance, and illustrate the interactions between SM and morphine, or SM and ß-endorphin, in anti-allodynia and anti-allodynic tolerance. Intrathecal SM exerted dose-dependent and long-lasting (>4 h) anti-allodynic effects in spinal nerve injury-induced neuropathic rats, with a maximal inhibition of 49% and a projected ED50 of 40.4 µg. SM and the peptidic GLP-1 receptor agonist exenatide treatments over 7 days did not induce self-tolerance to anti-allodynia or cross-tolerance to morphine or ß-endorphin. In contrast, morphine and ß-endorphin induced self-tolerance and cross-tolerance to SM and exenatide. In the spinal dorsal horn and primary microglia, SM significantly evoked ß-endorphin expression, which was completely prevented by the microglial inhibitor minocycline and p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. SM anti-allodynia was totally inhibited by the GLP-1 receptor antagonist exendin(9-39), minocycline, ß-endorphin antiserum, µ-opioid receptor antagonist CTAP, and SB203580. SM and exenatide specifically activated spinal p38 MAPK phosphorylation. These results indicate that SM reduces neuropathic pain by activating spinal GLP-1 receptors and subsequently stimulating microglial ß-endorphin expression via the p38 MAPK signaling. Stimulation of the endogenous ß-endorphin expression may be a novel and effective strategy for the discovery and development of analgesics for the long-term treatment of chronic pain.
Asunto(s)
Analgésicos/uso terapéutico , Medicamentos Herbarios Chinos/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacos , Microglía/efectos de los fármacos , Neuralgia/tratamiento farmacológico , betaendorfina/genética , Analgésicos/química , Animales , Animales Recién Nacidos , Células Cultivadas , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/química , Lateralidad Funcional , Péptido 1 Similar al Glucagón/metabolismo , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/fisiopatología , Masculino , Microglía/metabolismo , Minociclina/farmacología , Neuronas/efectos de los fármacos , Dimensión del Dolor/efectos de los fármacos , Preparaciones de Plantas/química , Preparaciones de Plantas/aislamiento & purificación , Preparaciones de Plantas/farmacología , Ratas , Ratas Wistar , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Nervios Espinales/lesiones , betaendorfina/metabolismoRESUMEN
We previously found that ultraviolet B (UVB) could stimulate the paraventricular nucleus (PVN) with activation the systemic hypothalamic-pituitary- adrenal (HPA) axis. To investigate whether UVB can also stimulate other hypothalamic nuclei, we tested its effect on the proopiomelanocortin (POMC) related signalling system in the arcuate nucleus (ARC) of female C57BL/6 and FVB albino mice. The shaved back skin of the mice was irradiated with either 100 or 400 mJ/cm2 of UVB. After 1, 3, 6 and 12 h, blood and hypothalamus were collected and processed for gene and protein expression, and measurement of α-MSH and ß-endorphin (ß-END) levels. An in situ immunohistochemical examination was performed for melanocortin receptor 4 (MC4R) and POMC-derived α-MSH. The expression of Pomc and MC4R mRNAs was stimulated, whereas that of AgRP was inhibited after exposure to UVB. It was accompanied by an increased number of both α-MSH- and MC4R-immunoreactive neurons in the ARC, and by increased levels of α-MSH and ß-END (both found in the hypothalamus and plasma). This surprising discovery of UVB stimulating the POMC system in the ARC, accompanied by the increased plasma levels of α-MSH and ß-END, paves the way for exciting areas of research on the communication between the skin and the brain, as well as is suggesting a new role for UVB in regulation of body metabolism.
Asunto(s)
Núcleo Arqueado del Hipotálamo/metabolismo , Proopiomelanocortina/biosíntesis , Piel/efectos de la radiación , Rayos Ultravioleta , Proteína Relacionada con Agouti/biosíntesis , Proteína Relacionada con Agouti/genética , Animales , Metabolismo Basal , Femenino , Regulación de la Expresión Génica/efectos de la radiación , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Proopiomelanocortina/genética , ARN Mensajero/biosíntesis , Receptor de Melanocortina Tipo 4/biosíntesis , Receptor de Melanocortina Tipo 4/genética , Transducción de Señal/fisiología , Organismos Libres de Patógenos Específicos , alfa-MSH/biosíntesis , alfa-MSH/sangre , alfa-MSH/genética , betaendorfina/biosíntesis , betaendorfina/sangre , betaendorfina/genéticaRESUMEN
The remarkable conservation of the primary structures and anatomical location of dogfish α-melanocyte-stimulating hormone (MSH), corticotrophin-like intermediate lobe peptide (CLIP) and adrenocorticotrophic hormone (ACTH) compared with mammals reinforced the tissue-specific processing hypothesis of ACTH peptides in the pituitary gland. The cloning of dogfish pro-opiomelanocortin (POMC) led to the identification of δ-MSH and simultaneously revealed the high conservation of the γ-MSH sequence during evolution. These studies have also shown that ß-MSH is much less conserved during evolution and in some species is not even processed from ß-LPH. Human pro-γ-MSH potentiates the corticosteroidogenic activity of ACTH and peptides generated from its N-terminal, in particular big-γ-MSH, appear to have adrenal mitogenic activity. Human big-γ-MSH (from the zona intermedia) may also cause the adrenache. The review finishes with a cautionary note with regard to the misdiagnosis of the ectopic ACTH syndrome in which partial processing of ACTH can result in large concentrations of α-MSH and CLIP, which can interfere in the performance of two-site immunoassays, and the problem of the correct disulphide bridge arrangement in synthetic N-POMC peptides is also discussed.